Morphinan alkaloid such as R-methylnaltrexone (abbreviated as MNTX) of the following structural formula:

as a μ-receptor antagonist in clinic, has useful pharmacological properties. It mainly binds to the receptors located at peripheral of gastrointestinal tract, acts as an antagonist, and can effectively alleviate unwanted side effects such as constipation and nausea during opiate treatment. Meanwhile, due to its ionic charge, it cannot cross blood-brain barrier and enter into central nervous system, so that the pain relief caused by the central activity of opiate will not be blocked by the existing quaternary derivatives.
The methods for preparing methylnaltrexone have been reported in earlier documents. For example, U.S. Pat. No. 4,176,186 and WO2004043964 disclose a method for preparing methylnaltrexone. The reaction scheme is as follows:

U.S. Pat. No. 4,176,186 discloses that methylnaltrexone is prepared by reacting naltrexone as raw material with methyl iodide in acetone as solvent in a closed vessel at 70° C. for 4 days to produce an iodide of MNTX after quaternization, and then performing an ion exchange. The two-step reaction has a yield of about 54%. The disadvantages of this method lie in that the raw material would not react completely; the raw material would form a salt and precipitate out during the process of the reaction; a qualified product would not be not ease to be obtained even after refining; moreover; and phenol alkylation byproducts would be generated.
WO2004043964 discloses a method for preparing methylnaltrexone by reacting naltrexone as raw material with methyl bromide under normal pressure in a dipolar solvent such as NMP (N-methyl-pyrrolidinone), and then performing a quaternization reaction. Although the problem that the raw material tends to precipitate when acetone is used as the solvent has been overcome by this method, and a good result has been obtained by performing the reaction under normal pressure or slight pressurization, it still has some disadvantages, for example: the raw material would not react completely; a phenol alkylation byproduct tends to occur; the reaction product usually is not a solid, but have to be obtained by forming a sodium salt and then subjecting to precipitation, and then acidization, which renders the refining a relatively low yield and complex operation for industrialization.
In order to overcome the drawback of the generation of phenol alkylation byproduct, WO2006127899 describes that methylnaltrexone is prepared by firstly protecting the phenol group with isobutyryl chloride, quaternizing with methyl iodide, and then hydrolysis and ion exchange. The reaction scheme is as follows:

Although the drawback that a phenol alkylation byproduct tends to occur has been overcome by this method, it still has shortages. For example, the esterification yield is not high (76.8%), and it requires to be purified by a column; when methyl iodide alone as a solvent is used for the quaternization reaction, it must be performed in a closed pressure vessel, and also requires to be purified by a column; the hydrolysis lasts for a long time, and the product is not well solidified with many impurities therein, thus the product has low purity and needs repeated refining. Furthermore, the amount of its isomer, that is, S-methylnaltrexone, is relatively high (2.69%) and the total yield in the case of such purity is only 38.5%. To provide a product with a higher purity, crystallization has to be repeated 4 or more times. Moreover, it imposes higher requirements on equipment for industrial production, the operation thereof is complicated, and multi-crystallization results in a decrease of yield and an increase of cost.
Therefore, there remains a need for more morphinan alkaloid derivatives and methods for preparing the same, especially for a more effective and more economic method for preparing R-methylnaltrexone.